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Molecular and Cellular Biology

Gun-Dong Kim, Riku Das, Xiaoquan Rao, Jixin Zhong, Jeffrey A Deiuliis, Diana L Ramirez-Bergeron, Sanjay Rajagopalan, Ganapati H Mahabeleshwar
Macrophages are strategically distributed in mammalian tissues and play an essential role in priming immune response. However, macrophages need to constantly strike a balance between activation and inhibition state to avoid a futile inflammatory reaction. Herein, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a potent repressor of macrophage pro-inflammatory activation. Gain- and loss-of-function studies revealed that CITED2 is required for optimal peroxisome proliferator-activated receptor gamma (PPARγ) activation and attendant select anti-inflammatory gene expression in macrophages...
December 4, 2017: Molecular and Cellular Biology
Piotr Grabarczyk, Passorn Winkler, Martin Delin, Praveen K Sappa, Sander Bekeschus, Petra Hildebrandt, Grzegorz K Przybylski, Uwe Völker, Elke Hammer, Christian A Schmidt
The BCL11B gene encodes a Krüppel-like, sequence-specific zinc finger transcription factor that acts as either a repressor or an activator, depending on its post-translational modifications. The importance of BCL11B in numerous biological processes in multiple organs has been well established in mouse knockout models. The phenotype of the first de novo monoallelic germline missense mutation in the BCL11B gene (N441K) strongly implies that the mutant protein acts in a dominant negative manner by neutralizing the unaffected protein through the formation of a nonfunctional dimer...
December 4, 2017: Molecular and Cellular Biology
A P Sudheesh, Rakesh S Laishram
Star-PAP, a nuclear phosphatidyl-inositol (PI) signal regulated poly(A) polymerase (PAP) couples with the type I PI phosphate kinase α (PIPKIα) and controls gene expression. We show that Star-PAP and PIPKIα together regulate 3'-end processing and expression of pre-mRNAs encoding key anti-invasive factors (KISS1R, CDH1, NME1, CDH13, FEZ1 and WIF1) in breast cancer. Consistently, endogenous Star-PAP level negatively co-relates with the cellular invasiveness of breast cancer cells. While silencing Star-PAP or PIPKIα increases cellular invasiveness in low-invasive MCF7 cells, Star-PAP overexpression decreases invasiveness in high-invasive MDA-MB-231 cells in a cellular Star-PAP level dependent manner...
December 4, 2017: Molecular and Cellular Biology
Alexander James Hale, Jeroen den Hertog
Regeneration of the zebrafish caudal fin following amputation occurs through wound healing, followed by formation of a blastema, which produces cells to replace the lost tissue in the final phase of regenerative outgrowth. We show that ptpn11a-/-ptpn11b-/- zebrafish embryos, lacking functional Shp2, fail to regenerate their caudal fin-folds. Rescue experiments indicate that Shp2a has a functional signalling role, requiring its catalytic activity and SH2 domains, but not the two C-terminal tyrosine phosphorylation sites...
December 4, 2017: Molecular and Cellular Biology
Tadashi Nakagawa, Masaki Hosogane, Makiko Nakagawa, Akane Morohoshi, Ryo Funayama, Keiko Nakayama
Recognition of gene promoters by RNA polymerase II is mediated by general transcription factor IID (TFIID), which has been thought to be a static complex and to play a passive role in the regulation of gene expression under the instruction of gene-specific transcription factors. Here we show that transforming growth factor--β (TGF-β) induced degradation of the TFIID subunit TAF7 in cultured mouse mammary epithelial cells and that this effect was required for proliferative arrest in response to TGF-β stimulation...
December 4, 2017: Molecular and Cellular Biology
Wi S Lai, Deborah J Stumpo, Lianqun Qiu, Roberta Faccio, Perry J Blackshear
Tristetraprolin (TTP) is a tandem CCCH zinc finger protein that can bind to AU-rich element-containing mRNAs and promote their decay. TTP knockout mice develop a severe inflammatory syndrome, largely due to excess tumor necrosis factor (TNF), whose mRNA is a direct target of TTP binding and destabilization. TTP's RNA binding activity, and its ability to promote mRNA decay, are lost when one of the zinc-coordinating residues of either zinc finger is mutated. To address several long-standing questions about TTP activity in intact animals, we developed a knock-in mouse with a cysteine to arginine mutation within the first zinc finger...
December 4, 2017: Molecular and Cellular Biology
Yi-Yu Wei, Hung-Ta Chen
Rpc34 is a subunit of the Rpc82/34/31 subcomplex residing on the DNA-binding cleft of RNA polymerase (pol) III. Rpc34 contains a structurally flexible N-terminal tandem winged-helix (tWH) domain related to the transcription factor TFIIE. While the second WH (WH2) fold of the tWH domain is known to function in DNA melting activity during transcription initiation, the functional role of the WH1 fold is unknown. In this study, we generated a series of new Rpc34 tWH mutants conferring a cold-sensitive growth phenotype...
November 27, 2017: Molecular and Cellular Biology
Danae Fonseca, Jorge Baquero, Michael R Murphy, Gamage Aruggoda, Sophia Varriano, Carmen Sapienza, Oksana Mashadova, Shadaqur Rahman, Frida E Kleiman
The cellular response to DNA damage is an intricate mechanism that involves the interplay among several pathways. In this study, we provide evidence of the role of the polyadenylation factor CstF-50 and the ubiquitin (Ub)-escort factor p97 as cofactors of BRCA1/BARD1 E3 Ub ligase, facilitating chromatin remodeling during DNA damage response (DDR). CstF-50 and p97 formed (a) complex(es) with BRCA1/BARD1, Ub and some of BRCA1/BARD1 substrates, such as RNA polymerase II (RNAP II) and histones. Besides, CstF-50 and p97 had an additive effect on the activation of the ubiquitination of these BRCA1/BARD1 substrates during DDR...
November 27, 2017: Molecular and Cellular Biology
Takuma Matsubara, Shoichiro Kokabu, Chihiro Nakatomi, Masayuki Kinbara, Toshihiro Maeda, Mitsuhiro Yoshizawa, Hisataka Yasuda, Teruko Takano-Yamamoto, Roland Baron, Eijiro Jimi
Osteoclasts resorb bone by attaching on the bone matrix and forming a sealing zone. In Src-deficient mice, osteoclasts cannot form the actin ring, a characteristic actin structure that seals the resorbed area, and hardly resorb any bone as a result. However, the molecular mechanism underlying the role of Src in the regulation and organization of the actin ring is still unclear. We identified an actin regulatory protein, protein phosphatase 1 regulatory subunit 18 (PPP1r18), as an Src-binding protein in an Src-, Yes-, and Fyn-deficient fibroblast (SYF) cell line overexpressing a constitutively active form of Src...
November 20, 2017: Molecular and Cellular Biology
Douglas G Baumann, Mu-Shui Dai, Hua Lu, David S Gilmour
The core promoter of protein-encoding genes plays a central role in regulating transcription. M1BP is a transcriptional activator that associates with a core promoter element known as Motif 1 that resides at thousand of genes in Drosophila. To gain insight into how M1BP functions, we identified an interacting protein called GFZF. GFZF had been previously identified in genetic screens for factors involved in maintenance of hybrid inviability, the G2-M DNA damage checkpoint, and RAS/MAPK signaling but its contribution to these processes was unknown...
November 20, 2017: Molecular and Cellular Biology
Dharini van der Hoeven, Kwang-Jin Cho, Yong Zhou, Xiaoping Ma, Wei Chen, Ali Naji, Dina Montufar-Solis, Yan Zuo, Sarah E Kovar, Kandice R Levental, Jeffrey A Frost, Ransome van der Hoeven, John F Hancock
KRAS must localize to the plasma membrane (PM) for biological activity. We show here that multiple acid sphingomyelinase (ASM) inhibitors, including tricyclic antidepressants, mislocalized phosphatidylserine (PtdSer) and KRASG12V from the PM; resulting in abrogation of KRASG12V signaling and potent, selective growth inhibition of mutant KRAS transformed cancer cells. Concordantly, in nude mice, the ASM inhibitor fendiline decreased the rate of growth of oncogenic KRAS-expressing MiaPaCa-2 tumors, but had no effect on the growth of the wild-type KRAS-expressing BxPC-3 tumors...
November 20, 2017: Molecular and Cellular Biology
Anup Mishra, Sneha Saxena, Anjali Kaushal, Ganesh Nagaraju
Mechanisms underlying mitochondrial genome maintenance have recently gained wide attention as mutations in mitochondrial DNA (mtDNA) lead to inherited muscular and neurological diseases which are linked to aging. It has been previously reported that human RAD51, RAD51C and XRCC3 localize to mitochondria upon oxidative stress and are required for the maintenance of mtDNA stability. Since RAD51 and RAD51 paralogs are spontaneously imported into mitochondria, their precise role in mtDNA maintenance during unperturbed conditions remains elusive...
November 20, 2017: Molecular and Cellular Biology
Weidan Peng, Narumi Furuuchi, Ludmila Aslanukova, Yu-Hung Huang, Samantha Z Brown, Wei Jiang, Sankar Addya, Vikalp Vishwakarma, Erika Peters, Jonathan R Brody, Dan A Dixon, Janet A Sawicki
Human antigen R (ELAVL1, HuR) is perhaps the best-characterized RNA-binding protein. Through its overexpression in various tumor types, HuR promotes post-transcriptional regulation of target genes in multiple core signaling pathways associated with tumor progression. The role of HuR overexpression in pancreatic tumorigenesis is unknown and led us to explore the consequences of HuR overexpression using a novel transgenic mouse model that has a >2-fold elevation of pancreatic HuR expression. Histologically, HuR overexpressing pancreas displays a fibro-inflammatory response and other pathological features characteristic of chronic pancreatitis...
November 13, 2017: Molecular and Cellular Biology
Hiroyuki Uechi, Erina Kuranaga, Tomohiro Iriki, Kohei Takano, Shoshiro Hirayama, Masayuki Miura, Jun Hamazaki, Shigeo Murata
Ubiquitin-mediated protein degradation plays essential roles in proteostasis and is involved in the pathogenesis of neurodegenerative diseases in which ubiquitin-positive aberrant proteins accumulate. However, how such aberrant proteins are processed inside cells has not been fully explored. Here, we show that the product of CG5445, a previously uncharacterized Drosophila gene, prevents accumulation of aggregate-prone ubiquitinated proteins. We found that ubiquitin conjugates were associated with CG5445, knockdown of which caused accumulation of detergent-insoluble ubiquitinated proteins...
November 6, 2017: Molecular and Cellular Biology
Venkatesh Kota, Gunhild Sommer, E Starr Hazard, Gary Hardiman, Jeffery L Twiss, Tilman Heise
The cancer associated RNA-binding protein La is posttranslationally modified by phosphorylation and sumoylation. Sumoylation of La not only regulates the trafficking of La in neuronal axons but also its association with specific mRNAs. Depletion of La in various types of cancer cell lines impairs cell proliferation, however, the molecular mechanism whereby La supports cell proliferation is not clearly understood.In this study, we address the question whether sumoylation of La contributes to cell proliferation of HEK293 cells...
October 30, 2017: Molecular and Cellular Biology
Laura Palanker Musselman, Jill L Fink, Ana R Grant, Jared A Gatto, Bryon F Tuthill, Thomas J Baranski
Systemic and tissue-specific insulin resistance have been described in Drosophila, and are accompanied by many indicators of metabolic disease. The downstream mediators of insulin-resistant pathophysiology remain unclear. We analyzed insulin signaling in the fat body using loss- and gain-of-function. When expression of the sole Drosophila Insulin receptor (InR) was reduced in larval fat bodies, animals exhibited developmental delay and reduced size in a diet-dependent manner. Fat body InR knockdown also led to reduced survival on high-sugar diets...
October 30, 2017: Molecular and Cellular Biology
Lina Heistinger, Brigitte Gasser, Diethard Mattanovich
The methylotrophic yeast Komagataella phaffii (Pichia pastoris) is homothallic and has been described to switch mating-type by an ancient inversion mechanism. Two mating-type (MAT) loci encode homologs of the MATa and MATα transcription factors, with the expression from one locus being downregulated by telomere position effects. However, not much is known about mating gene regulation since the mix of mating-types complicates detailed investigations. Within this study, we developed K. phaffii strains with stable mating-types by deletion of the inverted repeat region required for mating-type switching...
October 23, 2017: Molecular and Cellular Biology
Manpreet Kaur, Raksha Devi, Tanushree Ghosh, Md Muntaz Khan, Praveen Kumar, Priyanka, Ananya Kar, Aparna Sharma, Akhil Varshney, Vipin Kumar, Sandeep Saxena
The migration of chromosomes during mitosis is mediated primarily by kinesins that bind to the chromosomes and move along the microtubules, exerting pulling and pushing forces on the centrosomes. We report that a DNA replication protein, Sld5, localizes to the centrosomes resisting the microtubular pulling forces experienced during chromosome congression. In the absence of Sld5, centriolar satellites, which normally cluster around the centrosomes, are dissipated throughout the cytoplasm, resulting in the loss of their known function of recruiting the centrosomal protein, pericentrin...
October 23, 2017: Molecular and Cellular Biology
Lisheng Li, Hong Yang, Ting Li, Jinan Feng, Wanze Chen, Lu Ao, Xuying Shi, Yingying Lin, Haoyun Liu, Enrun Zheng, Qiaofa Lin, Jingjing Bu, Yanhua Zeng, Min Zheng, Yan Xu, Zhijun Liao, Jiacheng Lin, Yan He, Dexin Lin
The c-Jun gene encodes a transcription factor that has been implicated in many physiological and pathological processes. c-Jun is a highly unstable protein that is degraded through an ubiquitination/proteasome-dependent mechanism. However, the deubiquitinating enzyme (DUB) that regulates the stability of the c-Jun protein requires further investigation. Here, by screening a DUB expression library, we identified the ubiquitin-specific protease 6 (USP6) and showed that it regulates the stability of the c-Jun protein in a manner depending on its enzyme activity...
October 23, 2017: Molecular and Cellular Biology
Kewei Xie, Mingli Zhu, Peng Xiang, Xiaohuan Chen, Ayijiaken Kasimumali, Renhua Lu, Qin Wang, Shan Mou, Zhaohui Ni, Leyi Gu, Huihua Pang
Previous work showed that the activation of protein kinase A (PKA) signaling promoted mitochondrial fusion and prevented podocyte apoptosis. The cAMP response element binding protein (CREB) is the main downstream transcription factor of PKA signaling. Herein, we show that the pKA-agonist pCPT-cAMP prevented the production of adriamycin (ADR)-induced reactive oxygen species and apoptosis in podocytes, which were inhibited by CREB RNAi. The activation of PKA enhanced mitochondrial function and prevented the ADR-induced decrease of mitochondrial respiratory chain complex I subunits, NADH-ubiquinone oxidoreductase complex (ND) 1/3/4 genes, and protein expression...
October 16, 2017: Molecular and Cellular Biology
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